Approximately 20% of HIV-1-infected infected individuals develop neurological disease associated with the presence of HIV-1-infected cells in the brain. The effectiveness of high activity antiretroviral therapy (HAART) in markedly reducing plasma viral loads has raised the possibility that HIV infection may be successfully "purged" from the systemic immune system. However, HIV-1-infected cells in the brain may function as an important reservoir from which HIV can be reintroduced back into the lymphoid tissues after cessation of anti-retroviral therapy. Therefore, we propose to determine if the brain can function as an in vivo sanctuary for HIV-1-infected cells such as microglia that can migrate from the brain and infect peripheral lymphoid tissues. In addition, we will examine the in vivo effectiveness of a novel therapeutic approach consisting of HAART combined with targeted toxin therapy to reduce the numbers of HIV-1-infected cells in the brain. We also propose to study the mechanisms of the in vivo trafficking of HIV-1-infected cells into the brain. Although much is known about the clinical manifestations of HIVD, there are many gaps in our understanding of the pathophysiology of the disease including the mechanism by which HIV crosses the blood brain barrier. There is much data to support the possibility that HIV-1 infection is introduced into the brain by the infiltration of HIV- 1-infected cells. We will examine the mechanism of entry of HIV-1- infected cells by investigating the in vivo effect of different factors such as cellular activation, chemokine production and cytokine secretion on the migration of HIV-1-infected cells into the brain. Information generated from these studies should provide insights into the mechanism of cellular trafficking into the brain that may permit the development and in vivo testing of new therapeutic strategies aimed at preventing entry of HIV-1-infected cells into the brains. Blocking the migration of HIV-1-infected cells into the brain may be an important new therapeutic strategy to use for acutely infected individuals and for infants born to HIV-1-infected mothers. These in vivo studies will be performed using novel transgenic mouse models that we have recently developed that display productive HIV-1 infection.